ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.376T>A (p.Tyr126Asn) (rs200076893)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000524295 SCV000254369 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 126 of the MLH1 protein (p.Tyr126Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. This variant is present in population databases (rs200076893, ExAC 0.01%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individuals with clinical features of Lynch syndomre (PMID: 24383517,18561205, 30998989). ClinVar contains an entry for this variant (Variation ID: 90184). This variant has been reported not to substantially affect MLH1 protein function (PMID: 30998989). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000217922 SCV000279071 uncertain significance not provided 2018-09-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.376T>A at the cDNA level, p.Tyr126Asn (Y126N) at the protein level, and results in the change of a Tyrosine to an Asparagine (TAC>AAC). This variant was observed in at least one individual with early-onset, microsatellite instable colorectal cancer (Stigliano 2014). MLH1 Tyr126Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Tyr126Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000410157 SCV000489372 uncertain significance Lynch syndrome II 2016-09-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571582 SCV000662020 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000571582 SCV000684824 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000217922 SCV001134311 uncertain significance not provided 2019-07-02 criteria provided, single submitter clinical testing

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